Evidence for a lipoxygenase mechanism in the biosynthesis of epoxide and dihydroxy leukotrienes from 15(S)-hydroperoxyicosatetraenoic acid by human platelets and porcine leukocytes.

Abstract

Leukocyte preparations convert the hydroperoxy icosatetraenoic acids 5(S)-HPETE [hydroperoxyeicosatetraenoic acid] and 15(S)-HPETE to the unstable leukotriene epoxides LTA4 and 14,15-LTA4. In several ways, the conversion of 5- or 15-HPETE to leukotriene epoxide bears a formal mechanistic resemblance to the reaction catalyzed by the 12-lipoxygenase in the conversion of arachiodonic acid to 12(S)-HPETE. Points of similarity include enzymatic removal of a hydrogen at carbon 10, double bond isomerization, and formation of a new carbon-to-oxygen bond. In the case of 15(S)-HPETE, two 8,15- and an erythro-14,15-dihydroxy acid (8,15- and 14,15-DiHETE [dihydroxytetraenoic acids]), which result from incorporation of molecular oxygen to each hydroxyl group, are coproducts in the formation of 14,15-LTA4. The hypothesis that the biosynthesis of 14,15-LTA4 and of 8,15- and 14,15-DiHETE from 15(S)-HPETE occurs by a mechanism similar to that observed in lipoxygenase reactions was tested. Based on the results presented here, we conclude that the biosynthesis of 14,15-LTA4 and of 8,15- and 14,15-DiHETE from 15(S)-HPETE occurs via a common intermediate and that, moreover, the formation of these metabolites from 15(S)-HPETE is catalyzed by an enzyme with many mechanistic features in common with the 12-lipoxygenase.